tbuckley/cabot-search huggingface dataset:
The evolutionary and functional significance of germline immunoglobulin gene variation
Authors: Matt Pennell, Oscar L. Rodriguez, Corey T. Watson, Victor Greiff
Journal: Trends in Immunology (2022)

The recombination between immunoglobulin (IG) gene segments determines an individual's naïve antibody repertoire and, consequently, (auto)antigen recognition. Emerging evidence suggests that mammalian IG germline variation impacts humoral immune responses associated with vaccination, infection, and autoimmunity – from the molecular level of epitope specificity, up to profound changes in the architecture of antibody repertoires. These links between IG germline variants and immunophenotype raise the question on the evolutionary causes and consequences of diversity within IG loci. We discuss why the extreme diversity in IG loci remains a mystery, why resolving this is important for the design of more effective vaccines and therapeutics, and how recent evidence from multiple lines of inquiry may help us do so.
Biological Phenotyping in Sepsis and Acute Respiratory Distress Syndrome
Authors: Pratik Sinha, Nuala J. Meyer, Carolyn S. Calfee
Journal: Annual Review of Medicine (2022)

Heterogeneity in sepsis and acute respiratory distress syndrome (ARDS) is increasingly being recognized as one of the principal barriers to finding efficacious targeted therapies. The advent of multiple high-throughput biological data ("omics"), coupled with the widespread access to increased computational power, has led to the emergence of phenotyping in critical care. Phenotyping aims to use a multitude of data to identify homogenous subgroups within an otherwise heterogenous population. Increasingly, phenotyping schemas are being applied to sepsis and ARDS to increase understanding of these clinical conditions and identify potential therapies. Here we present a selective review of the biological phenotyping schemas applied to sepsis and ARDS. Further, we outline some of the challenges involved in translating these conceptual findings to bedside clinical decision-making tools.
Test-retest reliability, construct validity and determinants of 6-minute walk test performance in adult patients with asthma
Authors: R. Meys, S.M.J. Janssen, F.M.E. Franssen, A.W. Vaes, A.A.F. Stoffels, H.W.H. van Hees, B. van den Borst, P.H. Klijn, C. Burtin, A.J. van 't Hul, M.A. Spruit
Journal: Pulmonology (2022)

Current knowledge regarding the measurement properties of the 6-minute walk test (6MWT) in patients with asthma is limited. Therefore, the aim of this study was to assess the test-retest reliability, measurement error and construct validity of the 6MWT and identify determinants of 6-minute walk distance (6MWD) in patients with asthma.201 asthma patients referred for pre-pulmonary rehabilitation assessment, were retrospectively analyzed (age 61±12 years, 42% male, FEV1 78±27% predicted). Patients performed two 6MWTs on subsequent days using a 30 m straight walking course. Other measurements included resting dyspnea, maximal exercise capacity, body composition, pulmonary function, pulmonary and quadriceps muscle strength and symptoms of anxiety and depression. Measurement error (absolute reliability) was tested using standard error of measurement (SEM), minimal detectable change at 95% confidence interval (MDC95%) and Bland and Altman 95% limits of agreement, whereas test-retest reliability (relative reliability) and construct validity were assessed using the intra-class correlation coefficient (ICC2,1) and correlations, respectively.The 6MWD showed excellent test-retest reliability (ICC2,1: 0.91). The mean change in 6MWD after the second 6MWT was 18m (95%CI 11-24m), with 73% of the patients walking further in the second test. The SEM and MDC95% for the 6MWT were 35 m and 98 m, respectively. The best 6MWD correlated strongly with peak oxygen uptake during CPET and resting dyspnea (r = 0.61-0.64) and had no-to-moderate correlations with body composition, pulmonary function, respiratory and quadriceps muscle strength and symptoms of anxiety and depression (r = 0.02-0.45). Multiple linear regression was able to identify maximal workload, BMI, rollator use, maximal expiratory pressure, FEV1 and DLCO as independent determinants of the best 6MWD (R2 = 0.58).The 6MWT was considered to be reliable and valid in patients with asthma, which strengthens its clinical utility. However, the majority of patients demonstrated a considerable learning effect in the second 6MWT, providing a strong rationale for performing two 6MWTs.
CIS controls the functional polarization of GM-CSF-derived macrophages
Authors: Shengbo Zhang, Jai Rautela, Naiara G. Bediaga, Tatiana B. Kolesnik, Yue You, Junli Nie, Laura F. Dagley, Justin Bedo, Hanqing Wang, Li Sun, Robyn Sutherland, Elliot Surgenor, Nadia Iannarella, Rhys Allan, Fernando Souza-Fonseca-Guimaraes, Yi Xie, Qike Wang, Yuxia Zhang, Yuekang Xu, Stephen L. Nutt, Andrew M. Lew, Nicholas D. Huntington, Sandra E. Nicholson, Michaël Chopin, Yifan Zhan
Journal: Cellular and Molecular Immunology (2022)
Effects of Dapagliflozin on Hospitalizations in Patients With Chronic Kidney Disease
Authors: Meir Schechter, Niels Jongs, Glenn M. Chertow, Ofri Mosenzon, John J.V. McMurray, Ricardo Correa-Rotter, Peter Rossing, Anna Maria Langkilde, C. David Sjöström, Robert D. Toto, David C. Wheeler, Hiddo J.L. Heerspink
Journal: Annals of Internal Medicine (2022)

Acute hospitalizations are common in patients with chronic kidney disease (CKD) and often lead to decreases in health-related quality of life and increased care costs.To determine the effects of dapagliflozin on first hospitalizations and all (first and subsequent) hospitalizations and to explore effects on cause-specific hospitalizations.Post hoc analysis of a randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT03036150).386 ambulatory practice sites in 21 countries from 2 February 2017 through 12 June 2020.Adults with an estimated glomerular filtration rate of 25 to 75 mL/min/1.73 m2 and a urinary albumin-creatinine ratio of 200 to 5000 mg/g, with and without type 2 diabetes.Dapagliflozin, 10 mg once daily, or matching placebo (1:1 ratio).The effects of dapagliflozin on first hospitalizations for any cause, all hospitalizations, and cause-specific (first and recurrent) hospitalizations were determined. The reported system organ class was used to evaluate reasons for admission. Hospitalizations were analyzed using Cox proportional hazards regression models (first hospitalization), the Lin-Wei-Yang-Ying method (all hospitalizations or death), and negative binomial models (cause-specific hospitalizations).The study included 4304 patients (mean age, 61.8 years; 33.1% women). During a median follow-up of 2.4 years, 2072 hospitalizations were reported among 1224 (28.4%) participants. Compared with placebo, dapagliflozin reduced risk for a first hospitalization (hazard ratio, 0.84 [95% CI, 0.75 to 0.94]) and all hospitalizations or death (rate ratio, 0.79 [CI, 0.70 to 0.89]). There was no evidence that the effects of dapagliflozin on first and all hospitalizations varied by baseline presence of type 2 diabetes (P for interaction = 0.60 for each). Compared with placebo, dapagliflozin reduced the rate of admissions due to cardiac disorders, renal and urinary disorders, metabolism and nutrition disorders, and neoplasms.This was a post hoc analysis and should be viewed as hypothesis-generating. Hospitalizations and causes were reported by site investigators and were not centrally adjudicated.Dapagliflozin reduced the risk for hospitalization for any cause in patients with CKD with and without type 2 diabetes.AstraZeneca.
Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved
Authors: Stefan D. Anker, Javed Butler, Muhammad Shariq Usman, Gerasimos Filippatos, João Pedro Ferreira, Edimar Bocchi, Michael Böhm, Hans Pieter Brunner-La Rocca, Dong-Ju Choi, Vijay Chopra, Eduardo Chuquiure, Nadia Giannetti, Juan Esteban Gomez-Mesa, Stefan Janssens, James L. Januzzi, José R. González-Juanatey, Bela Merkely, Stephen J. Nicholls, Sergio V. Perrone, Ileana L. Piña, Piotr Ponikowski, Michele Senni, David Sim, Jindrich Spinar, Iain Squire, Stefano Taddei, Hiroyuki Tsutsui, Subodh Verma, Dragos Vinereanu, Jian Zhang, Tomoko Iwata, Janet M. Schnee, Martina Brueckmann, Stuart J. Pocock, Faiez Zannad
Journal: Nature Medicine (2022)

Abstract The EMPEROR-Preserved trial showed that the sodium–glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) &gt; 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) ( n = 4,005; 66.9%) or mid-range (41–49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71–0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66–1.04, P = 0.11). For patients with an LVEF of 41–49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57–0.88, P = 0.002) for the primary outcome ( P interaction = 0.27), and 0.57 (95%CI: 0.42–0.79, P &lt; 0.001) for total HHF ( P interaction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF &lt; 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.
Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer
Authors: Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie V. Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger
Journal: Cancer Discovery (2022)

Abstract Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. Significance: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247
High-Dose Cytarabine and Autologous Stem-Cell Transplantation in Mantle Cell Lymphoma: Long-Term Follow-Up of the Randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network
Authors: Olivier Hermine, Linmiao Jiang, Jan Walewski, André Bosly, Catherine Thieblemont, Michal Szymczyk, Christiane Pott, Gilles Salles, Pierre Feugier, Kai Hübel, Corinne Haioun, René Olivier Casasnovas, Christian Schmidt, Kamal Bouabdallah, Vincent Ribrag, Lothar Kanz, Jan Dürig, Bernd Metzner, David Sibon, Morgane Cheminant, Barbara Burroni, Wolfram Klapper, Wolfgang Hiddemann, Michael Unterhalt, Eva Hoster, Martin Dreyling
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In 2004, the European Mantle Cell Lymphoma (MCL) Network initiated the randomized open-label, phase III MCL Younger trial for first-line treatment of patients with advanced-stage MCL, age &lt; 66 years, comparing an alternating rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone/rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-CHOP/R-DHAP) induction followed by high-dose cytarabine-containing myeloablative radiochemotherapy conditioning and autologous peripheral blood stem-cell transplantation (R-DHAP arm) to R-CHOP with standard myeloablative radiochemotherapy and autologous stem-cell transplantation (R-CHOP arm). After a median follow-up of 10.6 years, the time to treatment failure was still significantly improved in the R-DHAP versus R-CHOP arms (medians 8.4 v 3.9 years, 5-/10-year rates 64%/46% v 41%/25%, P = .038, hazard ratio, 0.59). Median overall survival (OS) was not reached in the R-DHAP arm versus 11.3 years in R-CHOP arm (5-/10-year rates, 76%/60% v 69%/55%, P = .12). The unadjusted OS hazard ratios (0.80 [95% CI, 0.61 to 1.06], P = .12) reached significance when adjusted for Mantle Cell Lymphoma International Prognostic Index (MIPI) and MIPI + Ki-67 (MIPI-c) (0.74; 95% CI, 0.56 to 0.98; P = .038 and .60; 95% CI, 0.41 to 0.87; P = .0066). The incidence of secondary hematologic malignancies tended to be higher in the R-DHAP arm (4.5% v 1.4% at 10 years). With mature long-term data, we confirm the previously observed substantially prolonged time to treatment failure and, for the first time to our knowledge, show an improvement of OS. Some patients with MCL may be cured.
Extracellular CIRP dysregulates macrophage bacterial phagocytosis in sepsis
Authors: Mian Zhou, Monowar Aziz, Hao-Ting Yen, Gaifeng Ma, Atsushi Murao, Ping Wang
Journal: Cellular and Molecular Immunology (2022)

In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflammation. However, whether eCIRP regulates macrophage bacterial phagocytosis is unknown. Here, we reported that the bacterial loads in the blood and peritoneal fluid were decreased in CIRP-/- mice and anti-eCIRP Ab-treated mice after sepsis. Increased eCIRP levels were correlated with decreased bacterial clearance in septic mice. CIRP-/- mice showed a marked increase in survival after sepsis. Recombinant murine CIRP (rmCIRP) significantly decreased the phagocytosis of bacteria by macrophages in vivo and in vitro. rmCIRP decreased the protein expression of actin-binding proteins, ARP2, and p-cofilin in macrophages. rmCIRP significantly downregulated the protein expression of βPIX, a Rac1 activator. We further demonstrated that STAT3 and βPIX formed a complex following rmCIRP treatment, preventing βPIX from activating Rac1. We also found that eCIRP-induced STAT3 phosphorylation was required for eCIRP's action in actin remodeling. Inhibition of STAT3 phosphorylation prevented the formation of the STAT3-βPIX complex, restoring ARP2 and p-cofilin expression and membrane protrusion in rmCIRP-treated macrophages. The STAT3 inhibitor stattic rescued the macrophage phagocytic dysfunction induced by rmCIRP. Thus, we identified a novel mechanism of macrophage phagocytic dysfunction caused by eCIRP, which provides a new therapeutic target to ameliorate sepsis.
Unilateral Reduction of 18F-FDG Accumulation in Brown Adipose Tissue by Sympathectomy for Hyperhidrosis
Authors: Chigusa Shirakawa, Sho Koyasu, Masahiro Takada, Masakazu Toi, Yuji Nakamoto
Journal: Clinical Nuclear Medicine (2022)

A 30-year-old woman with left breast cancer underwent 18F-FDG PET/CT for staging. Intense FDG uptake was observed in the primary lesion, as well as on the left side of the neck to the supraclavicular fossa and left paravertebral region. History taking revealed that she had undergone a right thoracic sympathectomy for hyperhidrosis, which resulted in attenuated FDG uptake in the right-sided brown adipose tissue (BAT). With another examination keeping adequate warming, the accumulation of BAT was reduced and a diagnosis of cT1N1M0 was made. Unilateral sympathetic blockade can cause asymmetric FDG accumulation in BAT, which interferes with interpretation in tumors.
Use of Opioids for Adults With Pain From Cancer or Cancer Treatment: ASCO Guideline
Authors: Judith A. Paice, Kari Bohlke, Debra Barton, David S. Craig, Areej El-Jawahri, Dawn L. Hershman, Lynn R. Kong, Geana P. Kurita, Thomas W. LeBlanc, Sebastiano Mercadante, Kristina L. M. Novick, Ramy Sedhom, Carole Seigel, Joanna Stimmel, Eduardo Bruera
Journal: Journal of Clinical Oncology (2022)

To provide guidance on the use of opioids to manage pain from cancer or cancer treatment in adults.A systematic review of the literature identified systematic reviews and randomized controlled trials of the efficacy and safety of opioid analgesics in people with cancer, approaches to opioid initiation and titration, and the prevention and management of opioid adverse events. PubMed and the Cochrane Library were searched from January 1, 2010, to February 17, 2022. American Society of Clinical Oncology convened an Expert Panel to review the evidence and formulate recommendations.The evidence base consisted of 31 systematic reviews and 16 randomized controlled trials. Opioids have primarily been evaluated in patients with moderate-to-severe cancer pain, and they effectively reduce pain in this population, with well-characterized adverse effects. Evidence was limited for several of the questions of interest, and the Expert Panel relied on consensus for these recommendations or noted that no recommendation could be made at this time.Opioids should be offered to patients with moderate-to-severe pain related to cancer or active cancer treatment unless contraindicated. Opioids should be initiated PRN (as needed) at the lowest possible dose to achieve acceptable analgesia and patient goals, with early assessment and frequent titration. For patients with a substance use disorder, clinicians should collaborate with a palliative care, pain, and/or substance use disorder specialist to determine the optimal approach to pain management. Opioid adverse effects should be monitored, and strategies are provided for prevention and management.Additional information is available at www.asco.org/supportive-care-guidelines.
Epistatic Effects Between Amino Acid Insertions and Substitutions Mediate Toxin resistance of Vertebrate Na+,K+-ATPases
Authors: Shabnam Mohammadi, Halil İbrahim Özdemir, Pemra Ozbek, Fidan Sumbul, Josefin Stiller, Yuan Deng, Andrew J Crawford, Hannah M Rowland, Jay F Storz, Peter Andolfatto, Susanne Dobler
Journal: Molecular Biology and Evolution (2022)

Abstract The recurrent evolution of resistance to cardiotonic steroids (CTS) across diverse animals most frequently involves convergent amino acid substitutions in the H1-H2 extracellular loop of Na+,K+-ATPase (NKA). Previous work revealed that hystricognath rodents (e.g., chinchilla) and pterocliform birds (sandgrouse) have convergently evolved amino acid insertions in the H1-H2 loop, but their functional significance was not known. Using protein engineering, we show that these insertions have distinct effects on CTS resistance in homologs of each of the two species that strongly depend on intramolecular interactions with other residues. Removing the insertion in the chinchilla NKA unexpectedly increases CTS resistance and decreases NKA activity. In the sandgrouse NKA, the amino acid insertion and substitution Q111R both contribute to an augmented CTS resistance without compromising ATPase activity levels. Molecular docking simulations provide additional insight into the biophysical mechanisms responsible for the context-specific mutational effects on CTS insensitivity of the enzyme. Our results highlight the diversity of genetic substrates that underlie CTS insensitivity in vertebrate NKA and reveal how amino acid insertions can alter the phenotypic effects of point mutations at key sites in the same protein domain.
Increased 68Ga-FAPI Uptake in Psammomatous Meningioma in a Patient With Gallbladder Cancer
Authors: Dengsai Peng, Xiao Yang, Qin Yan, Weidong Gong, Yue Chen
Journal: Clinical Nuclear Medicine (2022)

A 70-year-old woman with a gallbladder mass was enrolled in our clinical trial of 68Ga-FAPI PET/CT study in tumors. Increased tracer uptake was noted in the gallbladder. In addition, focal uptake was localized in a lesion beside the falx cerebri. According to the location and radiological and clinical characteristics, a diagnosis of meningioma was made.
Effect of a Patient Decision Aid on Preferences for Colorectal Cancer Screening Among Older Adults
Authors: Alexandra F. Dalton, Carol E. Golin, Carolyn Morris, Christine E. Kistler, Rowena J. Dolor, Kaitlyn B. Bertin, Krithika Suresh, Swati G. Patel, Carmen L. Lewis
Journal: JAMA Network Open (2022)

Importance Guidelines recommend individualized decision-making for colorectal cancer (CRC) screening among adults aged 76 to 84 years, a process that includes a consideration of health state and patient preference. Objective To determine whether a targeted patient decision aid would align older adults’ screening preference with their potential to benefit from CRC screening. Design, Setting, and Participants This is a prespecified secondary analysis from a randomized clinical trial. Participants aged 70 to 84 years who were not up to date with screening and had an appointment within 6 weeks were purposively sampled by health state (poor, intermediate, or good) at 14 community-based primary care practices and block randomized to receive the intervention or control. Patients were recruited from March 1, 2012, to February 28, 2015, and these secondary analyses were performed from January 15 to March 1, 2022. Interventions Patient decision aid targeted to age and sex. Main Outcomes and Measures The primary outcome of this analysis was patient preference for CRC screening. The a priori hypothesis was that the decision aid (intervention) group would reduce the proportion preferring screening among those in poor and intermediate health compared with the control group. Results Among the 424 participants, the mean (SD) age was 76.8 (4.2) years; 248 (58.5%) of participants were women; and 333 (78.5%) were White. The proportion preferring screening in the intervention group was less than in the control group for those in the intermediate health state (34 of 76 [44.7%] vs 40 of 73 [54.8%]; absolute difference, −10.1% [95% CI, −26.0% to 5.9%]) and in the poor health state (24 of 62 [38.7%] vs 33 of 61 [54.1%]; absolute difference, −15.4% [95% CI, −32.8% to 2.0%]). These differences were not statistically significant. The proportion of those in good health who preferred screening was similar between the intervention and control groups (44 of 74 [59.5%] for intervention vs 46 of 75 [61.3%] for control; absolute difference, −1.9% [95% CI, −17.6% to 13.8%]). Conclusions and Relevance The findings of this secondary analysis of a clinical trial did not demonstrate statistically significant differences in patient preferences between the health groups. Additional studies that are appropriately powered are needed to determine the effect of the decision aid on the preferences of older patients for CRC screening by health state. Trial Registration ClinicalTrials.gov Identifier: NCT01575990